In this study we demonstrate for the first time that GSH could rapidly conjugate with dopamine (DA)-derived DA-o-quinones without enzymatic catalysis to form short-lived intermediate GSH-conjugates (2-S-GSH-DA-o-quinone and 5-S-GSH-DA-o-quinone). These intermediate GSH-conjugates are unstable and would finally form reactive or non-reactive GSH-conjugates dependent on ambient reductive forces. Under insufficient reductive forces, the intermediate GSH-conjugates could cyclize spontaneously to form reactive 7-S-GSH-aminochrome (7-S-GSH-AM). The 7-S-GSH-AM is so reactive that it could further react with another GSH to form 4,7-bi-GSH-5,6-dihydroindole. Its reactivity could also abrogate tyrosinase activity in solutions. In addition, the 7-S-GSH-AM could further undergo internal rearrangement to form non-reactive 7-S-GSH-5,6-dihydroindole. From these novel findings, we propose two detrimental positive feedback loops involving accelerated DA oxidation, increased GSH consumption and impaired GSH detoxification efficiency, as the underlying chemical explanation for dopaminergic neuron degeneration in Parkinson's disease
